This application is a continuation-in-part divisional of U.S. Ser. No. 750,323 filed June 28, 1985 by Mark S. Pasternack and Herman N. Eisen entitled "Cytotoxic T Lymphocyte Serine Esterase and Method for Stimulation and Inhibition", now U.S. Pat. No. 4,783,410 issued Nov. 8, 1988.
The vertebrate immune system is characterized by its ability to respond to an enormously diverse set of antigenic determinants. This capability is due to the synthesis by the body of a set of glycoproteins whose specificity for a single antigen is determined by a variable sequence of amino acids which binds to the antigen. The antigen-recognizing glycoproteins produced by B cells are called immunoglobulins. T cells or thymus derived lymphocytes are also capable of recognizing a wide range of different antigens. As in B cells, the ability to recognize a given antigen is also fixed in any particular clonal line. T cells, however, characteristically recognize only antigens located on the surfaces of cells in the specific molecular context of self major histocompatibility complex (MHC) gene products, not as freely circulating antigens. These cells provide a number of different mechanisms for defending the host against invasion by foreign substances and aid in limiting the frequency of tumors (neoplasms).
Unfortunately, these defense mechanisms can create problems, both when they are directed against their own host and when it becomes desirable to maintain foreign cells within the host, as in organ transplantation. Present immunosuppressive therapy following organ transplantation is based on corticosteroids and cyclosporine. In addition to their numerous non-immunologic side effects, these agents produce nonselective immunosuppression. As a result, life threatening infections, often due to pathogens of ordinarily low virulence ("opportunistic infections"), are a major problem in the management of allograft recipients. These problems are discussed by R.H. Rubin in "Infection in the renal transplant patient", Approach to Infection in the Compromised Host, R. H. Rubin and L. S. Young, eds., pp. 553-605 (New York, Plenum Medical Book Company, 1981). For example, cyclosporin has been associated with direct nephrotoxicity and an increased rate of lymphoid neoplasms.
When thymus-derived cells are stimulated by various agents, they differentiate into helper, suppressor, or cytotoxic T lymphocytes. Cytotoxic T lymphocytes (CTL) recognize and lyse target cells and are also thought to serve as an important source of defense against viral infections and possibly against neoplasms. A. E. Lukacher, V. L. Braciale, and T. J. Braciale in J. Exp. Med., 160, 814-824 (1984) and H. D. Engers, A. L. Glasebrook, and G. D. Sorenson in J. Exp. Med., 156, 1280-1285 (1982), review theories and supporting evidence.
The nature of the receptors responsible for antigen-recognition by these cells is rapidly becoming clarified, but the molecular mechanisms responsible for their cytolytic activity remain largely unknown. The possibility that proteases may be involved in this process has been suggested due to the effects of certain inhibitors. T-W Chang and H. N. Eisen, in J. Immunol., 124, 1028-1033 (1980) and D. Redelman and D. Hudig in J. Immunol., 124, 870-878(1980) demonstrated that the lytic activity of cytotoxic T lymphocytes (CTL) is reduced by exposure to certain protease inhibitors. Similar results have been shown for natural killer cells by D. Hudig, T. Haverty, C. Fulcher, D. Redelman, and J. Mendelsohn, in J. Immunol., 126, 1569-1574 (1981); P-C. Quan, T. Ishizaka, and B. R. Bloom in J. Immunol., 128, 1786-1791 (1982); and D. Hudig, D. Redelman, and L. Minning in J. Immunol., 133, 2647-2654 (1984).
In U.S. Ser. No. 750,323 filed June 28, 1985 by Mark S. Pasternack and Herman N. Eisen entitled "Cytotoxic T Lymphocyte Serine Esterase and Method for Stimulation and Inhibition", applicants described the isolation and characterization of a serine esterase having trypsin-like activity which is produced predominantly by cytotoxic T lymphocytes.
It is an object of the present invention to produce antibodies or other inhibitors to the serine esterase produced by the cytotoxic T lymphocytes.
Another object of the present invention is to produce nucleotide sequences encoding the serine esterase produced by the cytotoxic T lymphocytes, or portions thereof.
A further object of the present invention is to provide a means for inhibition of the cytolytic activity of the cytotoxic T lymphocytes.
A still further object of the present invention is to provide a mechanism for preventing and monitoring allograft rejection.